Progression of cancer in humans is associated with accumulation of genetic mutations. Most genes mutated in cancer are involved primarily in the maintenance of genomic integrity (Lengauer et al., Nature, 396:643, 1998) and the control of cell cycle progression (Sherr, Genes and Devel., 12:2984, 1998). These mutations in turn affect expression of a larger number of cellular genes which collectively are responsible for the changes in cell phenotype. Some of the differentially expressed genes function as oncogenes, while others behave as tumor suppressors to facilitate the development or progression of cancer (Weinberg, Annals of the New York Acad of Sci., 758:331, 1995). As the number of genes that are differentially expressed in cancer far exceed the number of mutated genes, they provide an abundant source of targets that can be exploited to dissect the complex changes that underlie cellular transformation.
Cancer genes are broadly classified into “oncogenes” which, when activated, promote tumorigenesis, and “tumor suppressor genes” which, when nonfunctional, fail to suppress tumorigenesis. While these classifications provide a useful method for conceptualizing tumorigenesis, it is also possible that a particular gene may play differing roles depending upon the particular allelic form of that gene, its regulatory elements, the genetic background and the tissue environment in which it is operating.
Oncogenes are somatic cell genes that are mutated from their wild-type alleles (the art refers to these wild-type alleles as protooncogenes) into forms which are able to induce tumorigenesis under certain conditions. There is presently a substantial literature on known and putative oncogenes and the various alleles of these oncogenes.
Tumor suppressor genes are genes that, in their wild-type alleles, express proteins that suppress abnormal cellular proliferation. When the gene coding for a tumor suppressor protein is mutated, deleted or transcriptionally nonfunctional, the resulting absence of wild-type tumor suppressor protein expression promotes abnormal cellular proliferation. A number of well-studied human tumors and tumor cell lines have been shown to have missing or nonfunctional tumor suppressor genes. Examples of tumor suppression genes include, but are not limited to, the retinoblastoma susceptibility gene or RB gene, the p53 gene, the deleted in colon carcinoma (DCC) gene and the neurofibromatosis type 1 (NF-1) tumor suppressor gene (Weinberg, R. A. Science, 1991, 254:1138). Loss of function or inactivation of tumor suppressor genes may play a central role in the initiation and/or progression of a significant number of human cancers.
The present invention shows that many cancers exhibit decreased EPLIN expression relative to their tissues of origin. The limitation and failings of the prior art to provide meaningful markers which correlate with the presence of cell proliferative disorders, such as cancer, has created a need for markers which can be used diagnostically, prognostically, and therapeutically over the course of such disorders. The present invention fulfills such a need.